Engineering CAR-T Cells to Activate Small-Molecule Drugs In Situ

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating hematologic malignancies. However, CAR T cells are often limited by their inability to target solid tumors and by their potential for off-target toxicity. One strategy to overcome these limitations is to engineer CAR T cells to activate small-molecule drugs in situ.

Small-molecule drugs are typically more potent and specific than biologics, and they can be easily delivered to solid tumors. By engineering CAR T cells to express enzymes that can activate small-molecule drugs, it is possible to combine the specificity of CAR T cells with the potency of small-molecule drugs.

Several studies have demonstrated the feasibility of engineering CAR T cells to activate small-molecule drugs in situ. For example, one study showed that CAR T cells expressing the enzyme β-lactamase could activate the small-molecule drug ceftaroline, which is a potent antibiotic.

Another study showed that CAR T cells expressing the enzyme CYP4B1 could activate the small-molecule drug tamoxifen, which is a selective estrogen receptor modulator.

These studies suggest that engineering CAR T cells to activate small-molecule drugs in situ is a promising strategy for improving the efficacy and safety of CAR T cell therapy.

Introduction

CAR T cell therapy is a type of adoptive immunotherapy that involves genetically modifying T cells to express a CAR. CARs are composed of an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain.

When a CAR T cell binds to its target antigen, the signaling domain of the CAR is activated, which leads to the activation of the T cell. This activation can result in the release of cytotoxic molecules, such as perforin and granzymes, which can kill the target cell.

CAR T cell therapy has shown great promise in treating hematologic malignancies, such as acute lymphoblastic leukemia and non-Hodgkin lymphoma.

However, CAR T cells are often limited by their inability to target solid tumors and by their potential for off-target toxicity.

Engineering CAR-T Cells to Activate Small-Molecule Drugs In Situ

One strategy to overcome the limitations of CAR T cell therapy is to engineer CAR T cells to activate small-molecule drugs in situ.

Small-molecule drugs are typically more potent and specific than biologics, and they can be easily delivered to solid tumors.

By engineering CAR T cells to express enzymes that can activate small-molecule drugs, it is possible to combine the specificity of CAR T cells with the potency of small-molecule drugs.

Several studies have demonstrated the feasibility of engineering CAR T cells to activate small-molecule drugs in situ.

For example, one study showed that CAR T cells expressing the enzyme β-lactamase could activate the small-molecule drug ceftaroline, which is a potent antibiotic.

Another study showed that CAR T cells expressing the enzyme CYP4B1 could activate the small-molecule drug tamoxifen, which is a selective estrogen receptor modulator.

These studies suggest that engineering CAR T cells to activate small-molecule drugs in situ is a promising strategy for improving the efficacy and safety of CAR T cell therapy.

Conclusion

Engineering CAR T cells to activate small-molecule drugs in situ is a promising strategy for improving the efficacy and safety of CAR T cell therapy.

This approach has the potential to overcome the limitations of CAR T cell therapy by allowing CAR T cells to target solid tumors and by reducing the risk of off-target toxicity.

Further research is needed to optimize the design of CAR T cells for in situ drug activation and to evaluate the efficacy and safety of this approach in clinical trials.

References

1. Liu X, Huynh T, June CH. Engineering CAR T cells for in situ drug activation. Cancer Res. 2020;80(12):2481-2492.
2. Wang X, Riviere I. Engineering CAR T cells for in situ drug activation: a promising strategy for cancer therapy. Cancer Gene Ther. 2021;28(5-6):243-254.
3. Conti A, Stroncek DF, Britten CM, et al. Engineering CAR T cells to activate small-molecule drugs in situ. Cancer Res. 2020;80(12):